After your arm has fallen asleep from an irregular posture, blood rushes back into the limb and nerves previously deprived of oxygen and electrolytes spontaneously regain function. During this process cellular and molecular processes within the ischemic limb may be producing bioactive restorative and regenerative compounds. Remote ischemic conditioning (RIC) is used to describe the process of transiently impeding blood flow to a limb and has shown to provide protection from subsequent major ischemic events in the brain and other organs. RIC can be achieved through a simple and cost-effective technique of applying a tourniquet to a limb for a pre-determined duration. Pre-clinical animal studies on RIC efficacy have been conducted in models of cardiac arrest and cerebral ischemia in which histopathological and functional outcomes have been improved by either pre-injury or post-injury RIC. Cerebral ischemia and traumatic brain injury (TBI), despite having dissimilar primary pathologies, share common secondary injury processes, including inflammation, oxidative stress, and blood-brain barrier permeability. Based on the pathological processes shared by TBI and cerebral ischemia, in this proposal, we test the hypothesis that remote ischemic conditioning (RIC) restores function following diffuse TBI and examine the potential mechanism of RIC action through a class of small lipids termed specialized pro-resolving mediators (SPMs). Aim 1 compares variations in RIC duration and timing in relation to midline fluid percussion brain injury in the rat. Following TBI and RIC, a battery of behavioral assays will be employed to assess the impact of RIC on attenuating the cognitive, sensory, and motor morbidities associated with TBI over a protracted time course. Aim 2, using the most successful variation of RIC identified in Aim 1, will evaluate the effect of RIC on the histopathological consequences of diffuse TBI. Following TBI and RIC, brains will be assessed for markers of neuropathology, inflammation, oxidative stress, and blood-brain barrier permeability. Aim 2 will provide insight into the potential mechanism(s) through which RIC provides protection from neurological injury. These studies can directly impact the course of understanding and treatment for the estimated 1.7 million traumatic brain injuries that occur annually in the United States. Ultimately, RIC could serve as a fast-acting invention for delivering endogenous restorative and reparative compounds to improve outcome from TBI.